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47677501.der.pdf
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47677501
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Dinotefuran
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165252-70-0
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044312
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Hoberman, A. (2009) Oral (Diet) Dosage-Range Finding Developmental Neurotoxicity and Immunotoxicity Study of MTI-446 (Dinotefuran) in Crl:CD (SD) Rats: Final Report.Project Number: SRY00001. Unpublished study prepared by Charles River Laboratories. 376 p.
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2009.0
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Dinotefuran: In a developmental immunotoxicity study and a dose-range finding for a developmental neurotoxicity study (DNT) (MRID 47677501), MTI-446 (dinotefuran; 94.7%; Lot # 2200210) was administered in the diet to presumed pregnant Sprague Dawley (Crl:CD[SD]) rats (10/dose) at dietary levels of 0, 1000, 3000, or 10,000 ppm (equivalent to 0, 105.4, 317.8, or 1035.4 mg/kg/day, respectively) beginning on gestation day (GD) 6, and continuing through lactation day (LD) 21. The F1 generation were potentially exposed through the maternal milk and the dam¿s dose formulation through weaning. On PND 21, the F1 generation were selected (up to three pups/sex/litter) randomly for immunotoxicity assays. F1 pups (20/sex/dose) were fed the same dietary concentrations as their dams beginning on PND 21 until termination (PND 42). Systemic toxicity parameters were evaluated in the P and F1 generations, and immunotoxicity was evaluated in the F1 generation. Ten F1 pups/sex/dose group were examined for humoral immune response by measuring IgM antibody forming cell responses following immunization with sheep red blood cell (SRBC); the remaining ten F1 pups/sex/dose group were examined for innate immune response by performing a natural killer (NK) cell assay. The splenocytes of the pups used for the NK cell assay were also phenotyped by flow cytometry.
For maternal toxicity, no treatment-related adverse effects were observed on mortality, clinical signs, body weights, body weight gains, food consumption, reproductive performance, or gross pathology.
The maternal toxicity LOAEL was not observed. The NOAEL for maternal toxicity is 10,000 ppm (equivalent to 1035.4 mg/kg bw/day).
For offspring toxicity, no treatment-related effects were observed on the birth, live birth, viability, or lactation indices or on sex ratio on PND 21. There were no clinical signs of toxicity, and all pups sacrificed on PND 4 and PND 21 appeared normal at necropsy. At 10,000 ppm, pup body weights were decreased (p¿0.01) by 13-18% during PND 13-21. After weaning, no treatment-related adverse effects were observed on mortality, clinical signs, food consumption, or gross pathology in the post-weaning F1 generation. At 10,000 ppm, post-weaning body weights were decreased (p¿0.05) by 7-22% during PND 22-57 in the males, and by 7-11% during PND 22-36 and PND 57-64 in the females.
The offspring toxicity LOAEL was 10,000 ppm (equivalent to 1035.4 mg/kg bw/day), based on decreased body weights in both sexes. The NOAEL for offspring toxicity is 3000 ppm (equivalent to 317.8 mg/kg bw/day).
For dose-range finding of a developmental neurotoxicity study, this diet concentration (10000 ppm) is considered suitable as a high dose level for the DNT study.
For developmental immunotoxicity, there were no treatment-related effects on antibody forming cell response (humoral immunity) and Natural Killer Cell activity (innate immunity). No differences that attributable to treatment were noted in the distribution of splenocyte subpopulations. Increased spleen weights were observed in the 1000 and 3000 ppm males, but this finding was not dose-dependent and was considered incidental.
Under conditions of this study, there were no immunologically adverse effects on antibody forming cell response or Natural Killer cell activity in male and female rats that [were] exposed to dinotefuran during the prenatal, postnatal and post-weaning period. The LOAEL for developmental immunotoxicity was not observed. The NOAEL is 10,000 ppm (equivalent to 1035.4 mg/kg bw/day).
This study is classified Acceptable/Non-guideline and provides information regarding the potential immunotoxic effect in offspring rats after exposure to dinotefuran during the prenatal, postnatal, and post-weaning periods. Additionally, it is a range-finding study for a definitive developmental neurotoxicity study.
[This classification scheme is applicable only to Developmental Neurotoxicity (DNT) studies. The DNT Work Group determined that this study can be classified as Acceptable. This study does not satisfy the guideline requirements for a developmental neurotoxicity study and is classified as NonGuideline pending review of all available positive control data. J. Rowland, 08/05/2009]
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Developmental-Neurotoxicity
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NA [870.6300, Developmental neurotoxicity study|870.7800, Immunotoxicity]
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Oral
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No Duration Period; GD 6 to LD 21; also Developmental Immunotoxicity study
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55238.0
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2009-08-05
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2018-10-17
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Added by
Madison Feshuk
on Apr 25, 2022
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